CN102659705A - Synthetic method of 3,4-disubstituted isoxazole compound - Google Patents
Synthetic method of 3,4-disubstituted isoxazole compound Download PDFInfo
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- 0 CC=C1N=CC[C@](C(*)C2N(CC3)C(C*)CC3C2)C1=CC#C Chemical compound CC=C1N=CC[C@](C(*)C2N(CC3)C(C*)CC3C2)C1=CC#C 0.000 description 8
- TZAPALQUKSLXSB-UHFFFAOYSA-N C(CC1)CN1C(C1c2ccccc2)ON=C1C1CCCCC1 Chemical compound C(CC1)CN1C(C1c2ccccc2)ON=C1C1CCCCC1 TZAPALQUKSLXSB-UHFFFAOYSA-N 0.000 description 1
- DZGNUJWWMXCBMG-UHFFFAOYSA-N CC(C)C1C(c2ccccc2)=NOC1N1CCCC1 Chemical compound CC(C)C1C(c2ccccc2)=NOC1N1CCCC1 DZGNUJWWMXCBMG-UHFFFAOYSA-N 0.000 description 1
- VJVNRBGTMJSTDW-UHFFFAOYSA-N CC(C)c1c[o]nc1-c1ccccc1 Chemical compound CC(C)c1c[o]nc1-c1ccccc1 VJVNRBGTMJSTDW-UHFFFAOYSA-N 0.000 description 1
- NNKVOGOHPCCQAQ-CLFYSBASSA-N O/N=C(/C1CCCCC1)\Cl Chemical compound O/N=C(/C1CCCCC1)\Cl NNKVOGOHPCCQAQ-CLFYSBASSA-N 0.000 description 1
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Abstract
The invention discloses a synthetic method of a 3,4-disubstituted isoxazole compound. The 3,4-disubstituted isoxazole compound is obtained by reacting an N-hydroxychloroimide compound, an aldehyde compound and secondary amine which are treated as reaction raw materials in a reaction solvent under the action of a base to obtain a 4,5-dihydroisoxazole compound, and oxidizing the 4,5-dihydroisoxazole compound under the action of an oxidant mCPBA. The 3,4-disubstituted isoxazole compound widely exists in medicinal active molecules and natural products, has very good biological activities and pharmacological activities, such as anticancer activities, antiallergic activities and antitumor activities, and also has very high medicinal values. The synthetic method which has the advantages of mild reaction conditions, easily available and cheap raw materials, simple operation and high yield is widely suitable for industrialized scale production.
Description
Technical field
It is a kind of 3 that the present invention is specifically related to, and the compound method of 4-two substituted isoxazoles compounds belongs to organic cpds process application technical field.
Background technology
3,4-two substituted isoxazoles compounds are one type of extremely important pharmaceutical-chemical intermediate, have very high using value.This type of product is present in pharmaceutical activity molecule and the natural product widely, has extraordinary biological activity and pharmacologically active, like antitumour activity, and antiallergic activity and anti-tumor activity, its pharmaceutical use is very high.Natural product and drug molecule with this core skeleton; For example: Antianaphylactic agent, Drug candidate for liver fibrosis, Cognitive enhancer; Leflunomide; Cloxacillin, NVP-AUY922 (anticancer drug) etc., shown in following:
Yet prior art is disclosed efficient synthetic 3, and the method for 4-two substituted isoxazoles compounds seldom and all needs perhaps polystep reaction, perhaps metal catalytic, and perhaps productive rate is very low.The present invention overcomes the above defective of prior art, and a kind of preparation 3 is provided, the novel method of 4-two substituted isoxazoles compounds.It is inexpensive that this method is simple, processing ease, raw material are easy to get, and product yield is high, and is very practical.
Summary of the invention
The object of the present invention is to provide a kind of synthetic 3; The novel method of 4-two substituted isoxazoles compounds; In reaction solvent, utilize the N-hydroxy chloride for imide analog compounds, aldehyde compound and secondary amine as reaction raw materials, under the effect of alkali; Reaction obtains 4,5-dihydro-isoxazole compounds.Then, under the effect of oxygenant mCPBA, oxidation obtains 3,4-two substituted isoxazoles compounds.
Reaction process is suc as formula shown in (I):
Wherein, R
1, R
2Be alkyl, naphthenic base, aryl, heterocycle; , R2 is Wasserstoffatoms, alkyl, naphthenic base, aryl, heterocycle; R
3, R
4Be alkyl, aryl, heterocycle becomes ring or Cheng Huan not between them.Among the present invention, R
1, R
2, R
3, R
4Include but are not limited to above-mentioned group.
Among the present invention, in reaction flask, secondary amine (substrate 3) (Z mmol) and alkali (W mmol) are dissolved in the U mL solvent, after temperature is transferred to V ℃, aldehyde compound (substrate 2) (Y mmol) are joined in the reaction.Then, the N-hydroxy chloride is dissolved in the RmL solvent for imide analog compounds (substrate 1) (X mmol), divides to join reaction system 5 times.Reaction is after 10 minutes down to be reflected at V ℃, and temperature transfers to room temperature, reacts 1.5 hours.TLC trace point plate, after reaction finished, the rapid column chromatography purifying obtained product 4 (4,5-dihydro-isoxazole compounds).(S mmol) is dissolved in the O mL solvent with product 4, adds 1.5 normal mCPBA, room temperature reaction P hour.TLC follows the tracks of reaction, and after raw material disappeared, rapid column chromatography obtained product 5 (3,4-two substituted isoxazoles compounds).
Among the present invention, said alkali is organic bases, comprising: triethylamine, diisopropyl ethyl amine, N-methylmorpholine; 4,4-Dimethylamino pyridine, pyrroles, cyclo-hexylamine, DBU; TBD, chiral proline and verivate thereof, golden pheasant soda and golden pheasant soda quaternary ammonium salt and verivate thereof, chiral D MAP verivate, chirality oxazole alkanones derivative; The chirality thiocarbamide, chiral amino acid, polypeptide compounds, and suc as formula the arbitrary compound shown in (1)-Shi (13)
Wherein: R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, R
11, R
12, R
13, R
14, R
15, R
16, R
17, R
18, R
19, R
20, R
21, R
22, R
23, R
24, R
25, R
26, R
27, R
28, R
29, R
30Alkyl can be, also aryl can be, can Cheng Huan between them, also Cheng Huan not.
Wherein, described secondary amine is the compound shown in formula (3a)-Shi (3g):
Wherein, R
1, R
2, R
3, R
4Be alkyl, naphthenic base, heterocycle or aryl; Ar
1, Ar
2Be various substituted aromatic rings.
Wherein, the consumption of said alkali is 1.0 equivalents-3.0 equivalents.
Wherein, said solvent is toluene, ether, THF, DCM, MeCN, MeOH, Brine.Involved in the present invention to solvent comprise but not only be confined to above-claimed cpd.
Wherein, described oxygenant is mCPBA, and its consumption reacts 1.5 equivalents of the compound 4 (4,5-dihydro-isoxazole compounds) that obtains down for the alkali effect.
Wherein, saidly be reflected at 0 ℃ to 50 ℃ and react.Preferably, temperature of reaction is 0 ℃ reacted 10 minutes down, or reacted 1.5 hours under the room temperature.
Wherein, the concentration of said substrate 1 (the N-hydroxy chloride is for imide analog compounds) is 0.05mol/L-1mol/L; Substrate 1 (the N-hydroxy chloride is for imide analog compounds): substrate 2 (aldehyde compound): substrate 3 (secondary amine)=1: (1-4): (1-4).Preferably, substrate 1: substrate 2: substrate 3=1: 4: 2.2.
Advantage of the present invention comprises: employed each raw material of compound method of the present invention is very simple, is the industriallization commodity, and wide material sources are cheap, and highly stable, do not need special preservation condition.Secondly, this compound method is simple, processing ease, product yield are high, and practicality is very strong.Moreover the present invention has the characteristic that cost is low, efficient is high, technology is simple, pollution is few, can carry out scale operation fully.
3 of the present invention's structure, 4-two substituted isoxazoles lopps compounds extensively are present in all kinds of high-activity natural products and the drug molecule, show different biological activitys, like antitumour activity, antiallergic activity and anti-tumor activity, its pharmaceutical use is very high.Utilize the present invention can be the high flux screening and the synthetic very practical new that provides of natural product of medicament research and development, small-molecule drug.
Embodiment
In conjunction with following specific embodiment, the present invention is done further detailed description, protection content of the present invention is not limited to following examples.Under spirit that does not deviate from inventive concept and scope, variation and advantage that those skilled in the art can expect all are included among the present invention, and are protection domain with the appending claims.The process of embodiment of the present invention, condition, reagent, experimental technique etc. except that the following content of mentioning specially, are the universal knowledege and the common practise of this area, and the present invention does not have special limiting content.The given data of following examples comprise concrete operations and reaction conditions and product.Product purity is identified through nuclear-magnetism.
Embodiment 1
The compound method of substrate 1:
Substrate A (10.0mmol) is dissolved in the pyridine of ethanol and 0.5mL of 10mL, is heated to 80 ℃.Stir after 5 minutes disposable adding oxammonium hydrochloride (12.0mmol).Reacted 2 hours down at 80 ℃, TLC plate detection reaction, substrate A is revolved and is desolvated after disappearing.Add 5mLDCM, 0oC stirred 10 minutes down, suspension liquid occurred.Solid filtering is fallen, revolve the dried product B that obtains to filtrating.(8.75mmol) is dissolved among the DCM of 10mL with product B, splashes into 5 pyridines, drops to 0oC and stirs 5 minutes.Then, in 30 minutes, add NCS (10.5mmol) in batches.After adding, reaction is warmed to room temperature, and stirring reaction disappears up to B.Add 20mL water and with the DCM extraction, column chromatography for separation obtains yellow powder product 1 (the N-hydroxy chloride is for imide analog compounds).
For example:
Substrate A 1 phenyl aldehyde (10.0mmol) is dissolved in the pyridine of ethanol and 0.5mL of 10mL, is heated to 80 ℃.Stir after 5 minutes disposable adding oxammonium hydrochloride (12.0mmol).Reacted 2 hours down at 80 ℃, TLC plate detection reaction, substrate A is revolved and is desolvated after disappearing.Add 5mL DCM, 0 ℃ was stirred 10 minutes down, suspension liquid occurs.Solid filtering is fallen, revolve the dried product B 1 (productive rate 96%) that obtains to filtrating.(8.75mmol) is dissolved among the DCM of 10mL with product B 1, splashes into 5 pyridines, drops to 0 ℃ and stirs 5 minutes.Then, in 30 minutes, add NCS (10.5mmol) in batches.After adding, reaction is warmed to room temperature, and stirring reaction disappears up to B.Add 20mL water and with the DCM extraction, column chromatography for separation obtains yellow powder product 1a (productive rate 85%).
Embodiment 2
In reaction flask, with substrate 3a (74.5 μ L, 0.88mmol) and TEA (53.9 μ tL 0.4mmol) are dissolved in the 4mL toluene, and after temperature was transferred to 0 ℃, (173.9 μ L 1.6mmol) joined in the reaction with substrate 2a.Then, (62.2mg 0.4mmol) is dissolved in the 0.2mL toluene, divides to join reaction system 5 times with substrate 1a.Reaction is after 10 minutes down to be reflected at 0 ℃, and temperature transfers to room temperature, reacts 1.5 hours.TLC trace point plate, after reaction finished, the rapid column chromatography purifying obtained product 4aa (100mg, 98%).
1H NMR (300MHz; CDCl
3): δ=7.75-7.69 (m, 2H), 7.48-7.41 (m, 3H), 5.41 (d, J=2.7Hz, 1H), 3.40 (dd; J=3.5,2.8Hz, 1H), 2.91-2.68 (m, 4H), 2.22-2.13 (m, 1H), 1.83-1.78 (m; 4H), 1.10 (d, J=6.9Hz, 3H), 0.83 (d, J=6.9Hz, 3H);
13C NMR (75MHz, CDCl
3): δ=157.2,129.6,128.8,126.8,95.3,56.2,46.9,28.1,23.8,20.6,17.1; HRMS (ESI) calcd for C
16H
23N
2O (M+H
+) 259.1805, found 259.1812.
Embodiment 3
Operation is with embodiment 2, and solvent uses THF, productive rate 93%.Detecting product through spectrogram is compound 4aa.
Embodiment 4
Operation is with embodiment 2, and solvent uses Et
2O, productive rate 97%.Detecting product through spectrogram is compound 4aa.
Embodiment 5
Operation is with embodiment 2, and solvent uses MeCN, productive rate 72%.Detecting product through spectrogram is compound 4aa.
Embodiment 6
Operation is with embodiment 2, and solvent uses MeOH, productive rate 58%.Detecting product through spectrogram is compound 4aa.
Embodiment 7
Operation is with embodiment 2, and solvent uses Brine, productive rate 39%.Detecting product through spectrogram is compound 4aa.
Embodiment 8
Operation is with embodiment 2, and solvent uses DCM, productive rate 99%.Detecting product through spectrogram is compound 4aa.
Embodiment 9
Operation is with embodiment 2. productive rates: 89%,
1H NMR (300MHz; CDCl
3): δ=7.71-7.63 (m, 2H), 7.43-7.36 (m, 3H), 5.76 (dd, J=9.7,4.0Hz, 1H), 3.40 (dd, J=17.5,9.7Hz, 1H), 3.13 (dd, J=17.5,4.1Hz, 1H), 2.89-2.67 (m, 4H), 1.78-1.75 (m, 4H);
13C NMR (75MHz, CDCl
3): δ=154.49,129.79,128.63,126.39,93.63,46.46,37.53,23.89; HRMS (ESI) calcd for C
13H
17N
2O (M+H
+) 217.1335, found217.1343.
Embodiment 10
Operation is with embodiment 2. productive rates: 84%,
1H NMR (300MHz; CDCl
3): δ=7.70-7.66 (m, 2H), 7.41-7.36 (m, 3H), 5.33 (d, J=2.5Hz, 1H), 3.35 (ddd, J=8.2,3.7,2.6Hz, 1H), 2.86-2.63 (m, 4H), 1.78-1.74 (m, 4H), 1.66-1.59 (m, 2H), 0.95 (t, J=7.4Hz, 3H);
13C NMR (75MHz, CDCl
3): δ=157.60,129.66,129.20,128.75,126.62,98.27,51.26,46.90,23.83,23.73,10.61; HRMS (ESI) calcd for C
15H
21N
2O (M+H
+) 245.1648, found 245.1660.
Embodiment 11
Operation is with embodiment 2. productive rates: 82%,
1H NMR (300MHz; CDCl
3): δ=7.70-7.65 (m, 2H), 7.42-7.37 (m, 3H), 5.34 (d, J=2.5Hz, 1H), 3.37 (ddd, J=8.7,3.6,2.5Hz, 1H), 2.85-2.62 (m, 4H), 1.78-1.72 (m, 4H), 1.68-1.38 (m, 4H), 0.91 (t, J=7.2Hz, 3H);
13C NMR (75MHz, CDCl
3): δ=157.90,129.65,129.24,128.77,126.63,98.73,50.04,46.93,33.02,23.76,19.92,13.95; HRMS (ESI) calcd for C
16H
23N
2O (M+H
+) 259.1805, found 259.1816.
Embodiment 12
Operation is with embodiment 2. productive rates: 84%,
1H NMR (300MHz; CDCl
3): δ=7.70-7.67 (m, 2H), 7.42-7.37 (m, 3H), 5.34 (d, J=2.4Hz, 1H), 3.36 (ddd, J=8.9,3.5,2.6Hz, 1H), 2.86-2.61 (m, 4H), 1.78-1.74 (m, 4H), 1.61-1.28 (m, 6H), 0.87 (t, J=7.0Hz, 3H);
13C NMR (75MHz, CDCl
3): δ=157.88,129.63,129.21,128.74,126.60,98.68,50.16,46.90,30.57,28.74,23.73,22.56,13.83; HRMS (ESI) calcd for C
17H
25N
2O (M+H
+) 273.1961, found 273.1968.
Embodiment 13
Operation is with embodiment 2. productive rates: 87%,
1H NMR (300MHz; CDCl
3): δ=7.69-7.66 (m, 2H), 7.42-7.37 (m, 3H), 5.33 (d, J=2.5Hz, 1H), 3.35 (ddd; J=8.8,3.5,2.5Hz, 1H), 2.85-2.62 (m, 4H), 1.78-1.73 (m; 4H), and 1.60-1.42 (m, 2H), 1.31-1.20 (m, 6H), 0.87-0.83 (m, 3H);
13C NMR (75MHz, CDCl
3): δ=157.87,129.63,129.20,128.74,126.60,98.65,50.21,46.90,31.63,30.81,26.28,23.72,22.38,13.91; HRMS (ESI) calcd for C
18H
27N
2O (M+H
+) 287.2118, found 287.2131.
Embodiment 14
Operation is with embodiment 2. productive rates: 98%,
1H NMR (300MHz; CDCl
3): δ=7.65-7.61 (m, 2H), 7.35-7.27 (m, 8H), 5.42 (d, J=2.8Hz, 1H), 4.43 (d, J=2.8Hz, 1H), 2.91-2.68 (m, 4H), 1.83-1.78 (m, 4H).;
13C NMR (75MHz, CDCl
3): δ=156.87,138.27,129.21,128.59,127.59,127.31,126.89,102.07,57.24,47.01,23.83; HRMS (ESI) calcd for C
19H
21N
2O (M+H
+) 315.1468, found 315.1471.
Embodiment 15
Operation is with embodiment 2. productive rates: 96%,
1H NMR (300MHz; CDCl
3): δ=7.73-7.70 (m, 2H), 7.43-7.38 (m, 3H), 7.32-7.20 (m, 5H), 5.38 (d; J=2.1Hz, 1H), 3.68 (ddd, J=9.7,4.5,2.1Hz, 1H); 3.09 (dd, J=14.5,4.5Hz, 1H), 2.81 (dd, J=14.4,9.7Hz; 1H), 2.77-2.55 (m, 4H), 1.72 (dd, J=9.8,3.6Hz, 4H);
13C NMR (75MHz, CDCl
3): δ=157.64,137.83,129.71,129.03,128.91,128.81,128.58,126.70,126.67,98.06,51.22,46.97,36.67,23.67; HRMS (ESI) calcd for C
20H
23N
2O (M+H
+) 307.1805, found 307.1805.
Embodiment 16
Operation is with embodiment 2. productive rates: 95%,
1H NMR (300MHz; CDCl
3): δ=7.60-7.55 (m, 4H), 7.39-7.34 (m, 6H), 5.52 (d, J=2.6Hz, 1H), 5.37 (d, J=2.4Hz, 1H), 3.57-3.41 (m, 2H), 2.91-2.58 (m, 8H), 1.82-1.74 (m, 8H);
13C NMR (75MHz, CDCl
3): δ=157.53,157.29,130.07,129.96,129.01,128.86,126.89,126.60,99.52,98.33,47.96,47.62,47.10,46.82,34.07,31.16,23.88,23.79; HRMS (ESI) calcd for C
27H
33N
4O
2(M+H
+) 445.2598, found 445.2603.
Embodiment 17
Operation is with embodiment 2. productive rates: 83%,
1H NMR (300MHz; CDCl
3): δ=8.18-7.79 (m, 4H), 7.41-7.21 (m, 5H), 5.55 (d, J=3.1Hz, 1H), 4.48 (d, J=3.1Hz, 1H), 2.95-2.71 (m, 4H), 1.87-1.83 (m, 4H);
13C NMR (75MHz, CDCl
3): δ=155.41,147.97,137.35,135.21,129.40,127.95,127.41,127.13,123.79,103.42,56.24,46.92,23.85; HRMS (ESI) calcd for C
19H
20N
3O
3(M+H
+) 338.1499, found338.1503.
Embodiment 18
Operation is with embodiment 2. productive rates: 80%,
1H NMR (300MHz; CDCl
3): δ=7.45-7.14 (m, 9H), 5.59 (d, J=3.5Hz, 1H), 4.90 (d, J=3.4Hz, 1H), 3.08-2.78 (m, 4H), 1.88-1.83 (m, 4H);
13C NMR (75MHz, CDCl
3): δ=157.53,137.73,132.39,131.71,130.42,130.30,128.97,128.48,127.51,127.42,127.36,127.33,126.75,102.52,58.27,47.23,24.04; HRMS (ESI) calcd for C
19H
20ClN
2O (M+H
+) 327.1259, found 327.1274.
Embodiment 19
Operation is with embodiment 2. productive rates: 81%,
1H NMR (300MHz; CDCl
3): δ=7.61-7.23 (m, 9H), 5.45 (d, J=2.8Hz, 1H), 4.44 (d, J=2.8Hz, 1H), 2.92-2.72 (m, 4H), 1.87-1.83 (m, 4H);
13C NMR (75MHz, CDCl
3): δ=156.02,137.86,135.60,130.15,129.27,128.85,128.08,128.03,127.89,127.74,127.47,127.23,102.29,57.00,46.97,23.82; HRMS (ESI) calcd for C
19H
20ClN
2O (M+H
+) 327.1259, found 327.1268.
Embodiment 20
Operation is with embodiment 2. productive rates: 86%;
1H NMR (300MHz; CDCl
3): δ=7.68-6.81 (m, 9H), 5.45 (d, J=3.0Hz, 1H), 4.85 (d, J=3.0Hz, 1H), 3.78 (s, 3H), 3.01-2.71 (m, 4H), 1.85-1.81 (m, 4H);
13CNMR (75MHz, CDCl
3): δ=157.33,138.64,130.93,130.34,128.76,128.62,127.37,127.13,120.75,111.23,101.40,58.72,55.29,47.10,23.87; HRMS (ESI) calcd for C
20H
23N
2O
2(M+H
+) 323.1754, found 323.1765.
Embodiment 21
Operation is with embodiment 2. productive rates: 83%,
1H NMR (300MHz; CDCl
3): δ=9.22 (d, J=8.6Hz, 1H), 7.85-7.78 (m, 2H), 7.66-7.46 (m, 3H), 7.35-7.20 (m, 6H), 5.48 (d, J=2.7Hz, 1H), 4.69 (d, J=2.8Hz, 1H), 3.02-2.79 (m, 4H), 1.86-1.82 (m, 4H);
13C NMR (75MHz, CDCl
3): δ=157.71,138.51,134.07,131.12,130.44,129.15,128.48,128.04,127.83,127.53,127.37,127.24,126.16,125.73,124.68,100.59,59.60,47.10,23.84; HRMS (ESI) calcd for C
23H
23N
2O (M+H
+) 343.1805, found 343.1802.
Embodiment 22
Operation is with embodiment 2. productive rates: 81%,
1H NMR (300MHz; CDCl
3): δ=7.36-7.23 (m, 6H), 7.00-6.98 (m, 1H), 6.91-6.88 (m, 1H), 5.44 (d, J=3.1Hz, 1H), 4.38 (d, J=3.1Hz, 1H), 2.93-2.68 (m, 4H), 1.83-1.79 (m, 4H);
13C NMR (75MHz, CDCl
3): δ=153.05,138.14,129.27,129.18,129.12,128.14,127.73,127.56,127.35,127.22,126.35,102.55,58.18,47.00,23.91; HRMS (ESI) calcd forC
17H
19N
2OS (M+H
+) 299.1213, found 299.1221.
Embodiment 23
Operation is with embodiment 2. productive rates: 77%,
1H NMR (300MHz; CDCl
3): δ=8.49-8.47 (m, 1H), 7.99-7.95 (m, 1H), 7.67-7.61 (m, 1H), 7.29-7.14 (m, 6H), 5.53 (d, J=2.8Hz, 1H), 4.79 (d, J=2.8Hz, 1H), 2.97-2.68 (m, 4H), 1.83-1.78 (m, 4H);
13C NMR (75MHz, CDCl
3): δ=158.98,149.32,138.65,136.12,128.72,127.47,127.13,123.71,121.96,102.80,55.83,46.94,23.84; HRMS (ESI) calcd for C
18H
20N
3O (M+H
+) 294.1601, found 294.1606.
Embodiment 24
Operation is with embodiment 2. productive rates: 98%,
1H NMR (300MHz; CDCl
3): δ=7.35-7.23 (m, 3H), 7.17-7.13 (m, 2H), 5.23 (d, J=2.8Hz, 1H); 3.98 (d, J=2.8Hz, 1H), 2.86-2.61 (m, 4H), 2.21-2.14 (m, 1H); 1.81-1.76 (m, 6H), 1.73-1.49 (m, 4H), 1.20-1.10 (m, 4H);
13C NMR (75MHz, CDCl
3): δ=163.06,138.44,129.00,127.46,127.39,100.08,58.32,46.99,36.52,31.52,30.13,26.00,25.81,25.72,23.79; HRMS (ESI) calcd for C
19H
27N
2O (M+H
+) 299.2118, found 299.2125
Embodiment 25
Operation is with embodiment 2. productive rates: 97%,
1H NMR (300MHz; CDCl
3): δ=5.11 (d, J=3.1Hz, 1H), 2.88 (dd, J=3.2,3.1Hz, 1H), 2.79-2.56 (m; 4H), and 2.26-2.16 (m, 1H), 2.06-1.88 (m, 5H), 1.76-1.72 (m, 4H), 1.29-1.22 (m; 6H), 1.01 (d, J=6.9Hz, 3H), 0.79 (d, J=7.0Hz, 3H);
13C NMR (75MHz, CDCl
3): δ=162.29,93.26,57.40,46.80,36.53,31.86,29.46,27.72,26.23,25.94,25.88,23.70,20.39,17.00; HRMS (ESI) calcd for C
16H
29N
2O (M+H
+) 265.2274, found 265.2281.
Embodiment 26
With product 4aa (129mg 0.5mmol) is dissolved in the 1mL solvent, add 1.5 normal mCPBA (129.4mg, 0.75mmol), room temperature reaction 4 hours.TLC follows the tracks of reaction, and after raw material disappeared, rapid column chromatography obtained product 5aa (88.8mg, 95%).
1H NMR (300MHz; CDCl
3): δ=8.23 (d, J=0.9Hz, 1H), 7.64-7.59 (m, 2H), 7.49-7.44 (m, 3H), 3.05-2.91 (m, 1H), 1.19 (d, J=6.8Hz, 6H);
13C NMR (75MHz, CDCl
3): δ=161.07,154.50,129.66,129.29,128.66,128.19,125.67,23.28,23.03; HRMS (ESI) calcd for C
12H
14NO (M+H
+) 188.1070, found 188.1066.
Embodiment 27
Operation is with embodiment 2, productive rate: 93%, and 1H NMR (300MHz; CDCl3): δ=8.58 (s, 1H), 8.25-8.20 (m, 2H), 7.72-7.68 (m, 2H), 7.41-7.37 (m, 3H), 7.25-7.22 (m, 2H); 13C NMR (75MHz, CDCl3): δ=158.36,156.95,148.47,134.94,129.50,129.04,128.85,128.56,128.02,123.77,120.47; HRMS (ESI) calcd for C15H11N2O3 (M+H+) 267.0764, found 267.0763.
Embodiment 28
One kettle way synthetic product 5aa:
In reaction flask, with substrate 3a (74.5 μ L, 0.88mmol) and TEA (53.9 μ L 0.4mmol) are dissolved in the 4mL toluene, and after temperature was transferred to 0 ℃, (173.9 μ L 1.6mmol) joined in the reaction with substrate 2a.Then, (62.2mg 0.4mmol) is dissolved in the 0.2mL toluene, divides to join reaction system 5 times with substrate 1a.Reaction is after 10 minutes down to be reflected at 0oC, and temperature transfers to room temperature, reacts 1.5 hours.(345.1mg, 2.0mmol), reaction is 3 hours under the room temperature for disposable then adding mCPBA.Rapid column chromatography obtains product 5aa, productive rate 82%.Detecting product through spectrogram is compound 5aa.
Claims (8)
1. one kind 3, the compound method of 4-two substituted isoxazoles compounds is characterized in that; In reaction solvent, with the N-hydroxy chloride for imide analog compounds, aldehyde compound and secondary amine as reaction raw materials, under the effect of alkali; Reaction obtains 4,5-dihydro-isoxazole compounds; Then, under the effect of oxygenant mCPBA, oxidation obtains 3,4-two substituted isoxazoles compounds; Reaction process is suc as formula shown in (I);
Formula (I);
Wherein, R
1, R
2Be alkyl, naphthenic base, aryl, heterocycle; , R2 is Wasserstoffatoms, alkyl, naphthenic base, aryl, heterocycle; R
3, R
4Be alkyl, aryl, heterocycle becomes ring or Cheng Huan not between them.
2. as claimed in claim 13, the compound method of 4-two substituted isoxazoles compounds is characterized in that described alkali is organic bases, comprising: triethylamine; Diisopropyl ethyl amine, N-methylmorpholine, 4,4-Dimethylamino pyridine, pyrroles; Cyclo-hexylamine, DBU, TBD, chiral proline and verivate thereof; Golden pheasant soda and golden pheasant soda quaternary ammonium salt and verivate thereof, chiral D MAP verivate, chirality oxazole alkanones derivative, chirality thiocarbamide; Chiral amino acid, polypeptide compounds, and the compound shown in formula (1)-Shi (13)
Wherein: R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, R
11, R
12, R
13, R
14, R
15, R
16, R
17, R
18, R
19, R
20, R
21, R
22, R
23, R
24, R
25, R
26, R
27, R
28, R
29, R
30Be alkyl or aryl; Can Cheng Huan between them, also Cheng Huan not.
3. as claimed in claim 13, the compound method of 4-two substituted isoxazoles compounds is characterized in that, described secondary amine is the compound shown in formula (3a)-Shi (3g):
Wherein, R
1, R
2, R
3, R
4Be alkyl, naphthenic base, heterocycle or aryl; Ar
1, Ar
2Be various substituted aromatic rings.
4. as claimed in claim 13, the compound method of 4-two substituted isoxazoles compounds is characterized in that, the consumption of said alkali is 1.0 equivalents-3.0 equivalents.
5. as claimed in claim 13, the compound method of 4-two substituted isoxazoles compounds is characterized in that, said solvent is toluene, ether, THF, DCM, MeCN, Me0H, Brine.
6. as claimed in claim 13, the compound method of 4-two substituted isoxazoles compounds is characterized in that, saidly is reflected at 0 ℃ to 50 ℃ and reacts.
7. as claimed in claim 13, the compound method of 4-two substituted isoxazoles compounds is characterized in that, said N-hydroxy chloride is 0.05mol/L-1mol/L for the concentration of imide analog compounds.
8. as claimed in claim 13, the compound method of 4-two substituted isoxazoles compounds is characterized in that, said N-hydroxy chloride is for imide analog compounds: aldehyde compound: secondary amine=1: (1-4): (1-4).
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|---|---|---|---|---|
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Non-Patent Citations (4)
| Title |
|---|
| 《Journal of the American Chemical Society》 20060324 Mase, N., Watanabe, K., Yoda, H., Takabe, K., Tanaka, F., & Barb Organocatalytic Direct Michael Reaction of Ketones and Aldehydes with beta-Nitrostyrene in Brine 第4966页第一栏第1段以及第一栏Electrophilic Addition to Enamine合成路线图,第二栏Table 1 1-8 第128卷, 第15期 * |
| MARTIN E. KUEHNE, SANDRA J. WEAVER, PETER FRAN: "Enamines as 1,3-Dipolarophiles", 《THE JOURNAL OF ORGANIC CHEMISTRY》 * |
| MASE, N., WATANABE, K., YODA, H., TAKABE, K., TANAKA, F., & BARB: "Organocatalytic Direct Michael Reaction of Ketones and Aldehydes with β-Nitrostyrene in Brine", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 * |
| MUNDY, B. P., ELLERD, M. G., & FAVALORO JR, F. G.: "《Name reactions and reagents in organic synthesis》", 31 December 2005, JOHN WILEY & SONS. * |
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